The majority of cancer-related deaths are associated with metastasis. The metastatic cascade is a complex process consisting of a number of important steps that include loss of tissue architecture, local invasion, invasion into blood and lymph vessels, extravasation, establishment of the secondary foci and angiogenesis. Very little is known about the mechanisms of metastasis. While it is clear the metastatic process is driven by genetic modifications in tumor cells, the identity of involved genes and their function remain unknown. The lack of mechanistic knowledge about metastasis represents a significant block on the road of development new and efficient therapies to treat cancer patients.
Animal models of human cancer are an important part of research directed toward finding a cure for cancer. Cancer development and especially formation of metastases at the distant organs is a complex process that is difficult to replicate using cells growing outside of the body (e.g., in an incubator). Genetically engineered mice have been used to model cancer development; however, a significant limitation of existing mouse models is an extremely low rate of metastasis formation, especially metastases to the bone. As a result, the metastatic process can not be replicated to study its mechanisms. In addition, the low frequency of metastasis in mouse models makes it difficult to test the efficacy of potential drugs for treatment of human patients with metastatic cancer.
Hepsin is a type-II transmembrane serine protease that is markedly upregulated in human prostate and ovarian cancer. For example, DNA microarray studies of gene expression in human prostate carcinomas have revealed marked overexpression of hepsin mRNA (Chen et al., J. Urol. 169:1316-1319 (2003); Dhanasekaran et al., Nature 412:822-826 (2001); Ernst et al., Am. J. Pathol. 160:2169-2180 (2002); Luo et al., Cancer Res. 61:4683-4688 (2001); Magee et al., Cancer Res. 61:5692-5696 (2001); Stamey et al., J. Urol. 166:2171-2177 (2001); Stephan et al., J. Urol. 171:187-191 (2004); Welsh et al., Cancer Res. 61:5974-5978 (2001)). Hepsin mRNA is upregulated in 90% of prostate tumors, with levels often increased greater than 10 fold, and exclusively expressed in tumor cells. Upregulation of hepsin RNA levels was reported to be accompanied by an increase in protein levels (Dhanasekaran et al., 2001). The significance of this upregulation and overall role of hepsin in cancer progression and metastasis is unknown, however. For example, it is not clear how hepsin mRNA levels correlate with different stages/grades of prostate cancer. Although initial studies showed that hepsin levels were highest in prostatic intraepithelial neoplasia (PIN) and decrease with prostate cancer progression (Dhanasekaran et al., 2001), other studies have demonstrated that hepsin mRNA levels increase with prostate cancer progression and reach maximum levels in more advanced (Gleason grade 4/5) prostate carcinomas (Chen et al., 2003; Stamey et al., 2001). At present, it is unclear if overexpression of hepsin in prostate cancer cells plays a role in prostate cancer development or progression.